KRAS-mutant lung adenocarcinoma represents a therapeutic dilemma owing to a dearth of effective treatment options that specifically target cancer cells with oncogenic KRAS mutations. Thoracic radiation therapy is used in many lung adenocarcinomas but there is little or no information on how to sensitize lung cancers to radiation, particularly in the context of individual tumor oncogenotypes. Based on prior work in this SPORE Project we have preliminary data that provide a rationale approach to this important problem using both human and transgenic mouse preclinical models (KRAS-mutant human orthotopic xenograft lung adenocarcinoma model, and KP, Kras-mutant/Tp53-mutant, mice, which develop metastatic lung adenocarcinomas owing to down-regulation of the microRNA-200 (miR-200) family). Based on these data, we hypothesize and plan to test that: (a) downstream signaling pathways activated by KRAS mutations and miR-200 down-regulation, namely those regulated by MAPK/ERK kinase (MEK1/2) and/or phosphatidylinositol 3-kinase (PI3K), are key mediators of radiation resistance in KRAS-mutant lung adenocarcinoma; and (b) KRAS codon 12 substitutions (G12D, G12V, and G12C) and microRNA-200 (miR- 200) family expression levels predict tumor cell sensitivity to PI3K targeted therapeutics. We propose to investigate these hypotheses with the following Specific Aims: Specific Aim 1: To carry out a mouse-human co-clinical trial with the MEK1/2 inhibitor Trametinib and examine mechanisms of acquired resistance to Trametinib. Specific Aim 2: To implement a human lung cancer clinical trial that examines whether Trametinib mediated MEK1/2 inhibition sensitizes KRAS-mutant lung adenocarcinomas to chemo-radiotherapy. Specific Aim 3: To examine whether specific KRAS codon 12 substitutions and/or miR-200 expression levels predict radiosensitization by PI3K pathway antagonism in our preclinical models. Findings from these studies on inhibitors of MEK1/2 and PI3K/mT0R as radiosensitizers can have immediate impact on personalizing lung cancer clinical care and lay the groundwork for future clinical trials. We have assembled a multidisciplinary team of applied and basic investigators fo ensure the success of this project.